U.S. Pat. No. 3,725,392 (Beal) discloses a process to produce various 9.alpha.-fluoro-16.beta.-alkylprednisolones including 9.alpha.-fluoro-16.beta.-methylprednisolone (betamethasone) which are known to be highly active anti-inflammatory agents. The prednisolone type steroids have a .DELTA..sup.1,4 -3-keto A ring. Beal discloses that the process can be performed on a prednisolone type compound (.DELTA..sup.1,4 -3-keto) or a cortisone type (.DELTA..sup.4 -3-keto) and the .DELTA..sup.1 double bond put in later. The first 2 steps of Beal are the transformation of a 11.beta.,21-dihydroxypregna-4,17(20)-dien-3-one to a 11.beta.,20,21-trihydroxypregna-4,16-dien-3-one. Example 1 of Beal discloses that starting with 165.2 g. (0.5 mole) of the .DELTA..sup.17 (20) compound, 51.1 g. (0.15 moles) of the .DELTA..sup.16 -21-ol is obtained, a 30% chemical yield. Beal's process involves photosensitized oxygenation followed by reduction. The process of the present invention accomplishes the transformation of a .DELTA..sup.17(20) steroid to a .DELTA..sup.16 steroid surprisingly and unexpectedly in about 89% yield, an almost 60% yield increase over Beal.
U.S. Pat. No. 3,281,415 discloses the transformation of a 17(20)-olefinic steroid to the corresponding .DELTA..sup.16 -20-keto steroid. Claim 20 claims a process of producing compounds of formulas (II and III) of the present invention. However, claim 20 of U.S. Pat. No. 3,281,415 claims photosensitized oxygenation whereas the process of the present invention uses a peracid and proceeds via an epoxide not a hydroperoxide. In column 30, at line 8 "11.beta.,20.alpha.,21-trihydroxy-1,4,16-pregnatrien-3-one 21-acetate" is disclosed as the starting material to prepare the corresponding 20-keto compound. However, the patent does not teach how to prepare this compound.
German Pat. No. 1,301,999 discloses a process for transforming a 17.alpha.,20.alpha.-epoxypregnane to a .DELTA..sup.16 -21-ol in about 90% yield by use of 1.82 equivalents of hydrogen bromide. The 10% impurity is the 17.beta.-bromide. The process of the present invention surprisingly and unexpectedly requires only about 0.03-0.05 equivalents of hydrogen bromide and produces less than 1% of the 17.beta.-bromide.
German Pat. No. 1,297,604 discloses a process for transforming a .DELTA..sup.17(20) -pregnane into a .DELTA..sup.16 -21-ol by peracid oxidation of the .DELTA..sup.17(20) -pregnane to the corresponding 17.alpha.,20.alpha.-epoxide which is then reacted with hydrogen iodide to form a 17.beta.-iodide which is then transformed to the .DELTA..sup.16 -21-ol. The process of the present invention involves peracid oxidation to form an epoxide, however the epoxide when reacted with the acid surprisingly and unexpectedly forms the .DELTA..sup.16 -20-ol directly without forming a 17.beta.-halide.